Coding and Noncoding Variation in LRRK2 and Parkinson's Disease Risk.
LRRK2
Parkinson's disease
association
genetics
Journal
Movement disorders : official journal of the Movement Disorder Society
ISSN: 1531-8257
Titre abrégé: Mov Disord
Pays: United States
ID NLM: 8610688
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
revised:
17
08
2021
received:
26
04
2021
accepted:
23
08
2021
pubmed:
21
9
2021
medline:
17
3
2022
entrez:
20
9
2021
Statut:
ppublish
Résumé
The leucine-rich repeat kinase 2 (LRRK2) gene harbors both rare highly damaging missense variants (eg, p.G2019S) and common noncoding variants (eg, rs76904798) with lower effect sizes that are associated with Parkinson's disease (PD) risk. This study aimed to investigate in a large meta-analysis whether the LRRK2 Genome-Wide Association Study (GWAS) signal represented by rs76904798 is independently associated with PD risk from LRRK2 coding variation and whether complex linkage disequilibrium structures with p.G2019S and the 5' noncoding haplotype account for the association of LRRK2 coding variants. We performed a meta-analysis using imputed genotypes from 17,838 patients, 13,404 proxy patients, and 173,639 healthy controls of European ancestry. We excluded carriers of p.G2019S and/or rs76904798 to clarify the role of LRRK2 coding variation in mediating disease risk and excluded carriers of relatively rare LRRK2 coding variants to assess the independence of rs76904798. We also investigated the co-inheritance of LRRK2 coding variants with p.G2019S, rs76904798, and p.N2081D. LRRK2 rs76904798 remained significantly associated with PD after excluding the carriers of relatively rare LRRK2 coding variants. LRRK2 p.R1514Q and p.N2081D were frequently co-inherited with rs76904798, and the allele distribution of p.S1647T significantly changed among patients after removing rs76904798 carriers. These data suggest that the LRRK2 coding variants previously related to PD (p.N551K, p.R1398H, p.M1646T, and p.N2081D) do not drive the 5' noncoding GWAS signal. These data, however, do not preclude the independent association of the haplotype p.N551K-p.R1398H and p.M1646T with altered disease risk. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.
Sections du résumé
BACKGROUND
The leucine-rich repeat kinase 2 (LRRK2) gene harbors both rare highly damaging missense variants (eg, p.G2019S) and common noncoding variants (eg, rs76904798) with lower effect sizes that are associated with Parkinson's disease (PD) risk.
OBJECTIVES
This study aimed to investigate in a large meta-analysis whether the LRRK2 Genome-Wide Association Study (GWAS) signal represented by rs76904798 is independently associated with PD risk from LRRK2 coding variation and whether complex linkage disequilibrium structures with p.G2019S and the 5' noncoding haplotype account for the association of LRRK2 coding variants.
METHODS
We performed a meta-analysis using imputed genotypes from 17,838 patients, 13,404 proxy patients, and 173,639 healthy controls of European ancestry. We excluded carriers of p.G2019S and/or rs76904798 to clarify the role of LRRK2 coding variation in mediating disease risk and excluded carriers of relatively rare LRRK2 coding variants to assess the independence of rs76904798. We also investigated the co-inheritance of LRRK2 coding variants with p.G2019S, rs76904798, and p.N2081D.
RESULTS
LRRK2 rs76904798 remained significantly associated with PD after excluding the carriers of relatively rare LRRK2 coding variants. LRRK2 p.R1514Q and p.N2081D were frequently co-inherited with rs76904798, and the allele distribution of p.S1647T significantly changed among patients after removing rs76904798 carriers.
CONCLUSIONS
These data suggest that the LRRK2 coding variants previously related to PD (p.N551K, p.R1398H, p.M1646T, and p.N2081D) do not drive the 5' noncoding GWAS signal. These data, however, do not preclude the independent association of the haplotype p.N551K-p.R1398H and p.M1646T with altered disease risk. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.
Identifiants
pubmed: 34542912
doi: 10.1002/mds.28787
pmc: PMC9292230
doi:
Substances chimiques
LRRK2 protein, human
EC 2.7.11.1
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
EC 2.7.11.1
Types de publication
Journal Article
Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
95-105Subventions
Organisme : Medical Research Council
ID : G1100643
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : R01 CA141668
Pays : United States
Organisme : NIA NIH HHS
ID : K24 AG000949
Pays : United States
Organisme : Intramural NIH HHS
ID : Z01 ES101986
Pays : United States
Organisme : Department of Health
Pays : United Kingdom
Organisme : Wellcome Trust
ID : WT089698/Z/09/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 085475
Pays : United Kingdom
Organisme : Intramural NIH HHS
ID : Z01 AG000949
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Intramural NIH HHS
ID : ZIA NS003154
Pays : United States
Organisme : Wellcome Trust
ID : 090355
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 076113
Pays : United Kingdom
Organisme : Wellcome Trust
ID : WT089698
Pays : United Kingdom
Organisme : NINDS NIH HHS
ID : R01 NS037167
Pays : United States
Organisme : Medical Research Council
ID : G0700943
Pays : United Kingdom
Organisme : NINDS NIH HHS
ID : P50 NS071674
Pays : United States
Informations de copyright
© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.
Références
NPJ Parkinsons Dis. 2017 Mar 28;3:11
pubmed: 28649611
Hum Mutat. 2010 May;31(5):561-8
pubmed: 20186690
Nat Genet. 2016 Oct;48(10):1284-1287
pubmed: 27571263
Hum Mol Genet. 2007 Sep 1;16(17):2031-9
pubmed: 17584768
Lancet Neurol. 2019 Dec;18(12):1091-1102
pubmed: 31701892
Neurol Genet. 2019 Jul 09;5(4):e348
pubmed: 31404238
Biomed Res Int. 2015;2015:678701
pubmed: 25821816
Mol Neurodegener. 2017 Jan 19;12(1):9
pubmed: 28103901
Mov Disord. 2021 Aug;36(8):1795-1804
pubmed: 33960523
Neurobiol Aging. 2021 Jul;103:142.e1-142.e5
pubmed: 33781610
Bioinformatics. 2010 Sep 1;26(17):2190-1
pubmed: 20616382
PLoS Negl Trop Dis. 2016 Feb 04;10(2):e0004412
pubmed: 26844546
Nature. 2018 Oct;562(7726):203-209
pubmed: 30305743
Front Mol Neurosci. 2016 Mar 08;9:18
pubmed: 27013965
Ann Neurol. 2008 Jul;64(1):88-92
pubmed: 18412265
PLoS One. 2013 Aug 13;8(8):e70724
pubmed: 23967090
Biochem Soc Trans. 2019 Dec 20;47(6):1581-1595
pubmed: 31769472
Biochem Soc Trans. 2019 Apr 30;47(2):651-661
pubmed: 30837320
Genes Immun. 2015 Mar;16(2):112-9
pubmed: 25521227
Hum Mol Genet. 2012 Nov 15;21(22):4966-79
pubmed: 22899650
Hum Mol Genet. 2021 Apr 30;30(6):454-466
pubmed: 33640967
Am J Neurodegener Dis. 2013 Nov 29;2(4):287-99
pubmed: 24319646
Nat Neurosci. 2006 Oct;9(10):1231-3
pubmed: 16980962
Neuron. 2004 Nov 18;44(4):595-600
pubmed: 15541308
Ann Neurol. 2012 Mar;71(3):370-84
pubmed: 22451204
Sci Transl Med. 2017 Dec 20;9(421):
pubmed: 29263232
Neurology. 2014 Dec 9;83(24):2256-61
pubmed: 25378673
Neuron. 2004 Nov 18;44(4):601-7
pubmed: 15541309
Nat Rev Neurol. 2020 Feb;16(2):97-107
pubmed: 31980808
Nat Immunol. 2011 Oct 09;12(11):1063-70
pubmed: 21983832
Parkinsonism Relat Disord. 2007 Dec;13(8):509-15
pubmed: 17540608
Lancet Neurol. 2008 Jul;7(7):583-90
pubmed: 18539534
Proc Natl Acad Sci U S A. 2005 Nov 15;102(46):16842-7
pubmed: 16269541
PLoS One. 2013 Dec 05;8(12):e82001
pubmed: 24339985
Nat Genet. 2021 Jul;53(7):942-948
pubmed: 34183854
J Neuroimmune Pharmacol. 2020 Dec;15(4):794-800
pubmed: 32180132
Lancet Neurol. 2021 Feb;20(2):107-116
pubmed: 33341150
Parkinsonism Relat Disord. 2007 Mar;13(2):89-92
pubmed: 17222580
Bioinformatics. 2010 Sep 15;26(18):2336-7
pubmed: 20634204
Sci Transl Med. 2018 Jan 10;10(423):
pubmed: 29321258
Sci Adv. 2020 Nov 11;6(46):
pubmed: 33177079
Neurobiol Dis. 2006 Aug;23(2):329-41
pubmed: 16750377
Parkinsonism Relat Disord. 2012 Jul;18(6):722-30
pubmed: 22575234
Nat Commun. 2019 Mar 1;10(1):994
pubmed: 30824768
Parkinsonism Relat Disord. 2021 Feb;83:22-30
pubmed: 33454605
Cells. 2021 Jan 05;10(1):
pubmed: 33466414
Lancet Neurol. 2011 Oct;10(10):898-908
pubmed: 21885347
Neurogenetics. 2006 Jul;7(3):133-8
pubmed: 16633828